Vigorous Exercise in Patients With Congenital Long QT Syndrome: Results of the Prospective, Observational, Multinational LIVE-LQTS Study.

BACKGROUND: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. METHODS: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis. RESULTS: Among the 1413 participants (13% <18 years of age, 35% 18-25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57-1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67-2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup. CONCLUSIONS: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02549664.

Long QT syndrome: importance of reassessing arrhythmic risk after treatment initiation.

BACKGROUND AND AIMS: Risk scores are proposed for genetic arrhythmias. Having proposed in 2010 one such score (M-FACT) for the long QT syndrome (LQTS), this study aims to test whether adherence to its suggestions would be appropriate. METHODS: LQT1/2/3 and genotype-negative patients without aborted cardiac arrest (ACA) before diagnosis or cardiac events (CEs) below age 1 were included in the study, focusing on an M-FACT score ≥2 (intermediate/high risk), either at presentation (static) or during follow-up (dynamic), previously associated with 40% risk of implantable cardioverter defibrillator (ICD) shocks within 4 years. RESULTS: Overall, 946 patients (26 ± 19 years at diagnosis, 51% female) were included. Beta-blocker (ßB) therapy in 94% of them reduced the rate of those with a QTc ≥500 ms from 18% to 12% (P < .001). During 7 ± 6 years of follow-up, none died; 4% had CEs, including 0.4% with ACA. A static M-FACT ≥2 was present in 110 patients, of whom 106 received ßBs. In 49/106 patients with persistent dynamic M-FACT ≥2, further therapeutic optimization (left cardiac sympathetic denervation in 55%, mexiletine in 31%, and ICD at 27%) resulted in just 7 (14%) patients with CEs (no ACA), with no CEs in the remaining 57. Additionally, 32 patients developed a dynamic M-FACT ≥2 but, after therapeutic optimization, only 3 (9%) had CEs. According to an M-FACT score ≥2, a total of 142 patients should have received an ICD, but only 22/142 (15%) were implanted, with shocks reported in 3. CONCLUSIONS: Beta-blockers often shorten QTc, thus changing risk scores and ICD indications for primary prevention. Yearly risk reassessment with therapy optimization leads to fewer ICD implants (3%) without increasing life-threatening events.

Proof of concept for monoclonal antibody therapy in a cellular model of acquired long QT syndrome type 3.

Long QT syndrome (LQTS) type 3 although less common than the first two forms, differs in that arrhythmic events are less likely triggered by adrenergic stimuli and are more often lethal. Effective pharmacological treatment is challenged by interindividual differences, mutation dependence, and adverse effects, translating into an increased use of invasive measures (implantable cardioverter-defibrillator, sympathetic denervation) in patients with LQTS type 3. Previous studies have demonstrated the therapeutic potential of polyclonal KCNQ1 antibody for LQTS type 2. Here, we sought to identify a monoclonal KCNQ1 antibody that preserves the electrophysiological properties of the polyclonal form. Using hybridoma technology, murine monoclonal antibodies were generated, and patch clamp studies were performed for functional characterization. We identified a monoclonal KCNQ1 antibody able to normalize cardiac action potential duration and to suppress arrhythmias in a pharmacological model of LQTS type 3 using human-induced pluripotent stem cell-derived cardiomyocytes.NEW & NOTEWORTHY Long QT syndrome is a leading cause of sudden cardiac death in the young. Recent research has highlighted KCNQ1 antibody therapy as a new treatment modality for long QT syndrome type 2. Here, we developed a monoclonal KCNQ1 antibody that similarly restores cardiac repolarization. Moreover, the identified monoclonal KCNQ1 antibody suppresses arrhythmias in a cellular model of long QT syndrome type 3, holding promise as a first-in-class antiarrhythmic immunotherapy.

Fetal Long QT Syndrome - Challenges in Perinatal Management: A Review and Case Report. Induction of Labor and Vaginal Birth Under Continuous Magnesium Therapy.

Congenital LQTS is an often undetected inherited cardiac channel dysfunction and can be a reason for intrauterine fetal demise. It can present in utero as CTG and ultrasound abnormalities, i. e., bradycardia, ventricular tachycardia, or fetal hydrops. Diagnosis is made by CTG, echocardiography, or fMCG. Intrauterine therapy with a ß blocker and i. v. magnesium should be started. Our objective was to examine the current knowledge about diagnosis and treatment of LQTS and in particular to highlight the opportunity of vaginal birth under continuous intravenous magnesium therapy. Therefore, a thorough MEDLINE and Google Scholar search was conducted. Randomized controlled trials, meta-analyses, prospective and retrospective cohort trials, and case reports were considered. We showed the possibility of vaginal delivery under continuous magnesium therapy in a case of suspected fetal LQTS. A stepwise concept for diagnosis, monitoring, and peripartum management in low, intermediate, and high risk cases of fetal LQTS is presented. If risk is low or intermediate, a vaginal delivery under continuous monitoring is reasonable. Induction of labor at term should be evaluated.

Unraveling Complexities in Genetically Elusive Long QT Syndrome.

Genetic testing has become standard of care for patients with long QT syndrome (LQTS), providing diagnostic, prognostic, and therapeutic information for both probands and their family members. However, up to a quarter of patients with LQTS do not have identifiable Mendelian pathogenic variants in the currently known LQTS-associated genes. This absence of genetic confirmation, intriguingly, does not lessen the severity of LQTS, with the prognosis in these gene-elusive patients with unequivocal LQTS mirroring genotype-positive patients in the limited data available. Such a conundrum instigates an exploration into the causes of corrected QT interval (QTc) prolongation in these cases, unveiling a broad spectrum of potential scenarios and mechanisms. These include multiple environmental influences on QTc prolongation, exercise-induced repolarization abnormalities, and the profound implications of the constantly evolving nature of genetic testing and variant interpretation. In addition, the rapid advances in genetics have the potential to uncover new causal genes, and polygenic risk factors may aid in the diagnosis of high-risk patients. Navigating this multifaceted landscape requires a systematic approach and expert knowledge, integrating the dynamic nature of genetics and patient-specific influences for accurate diagnosis, management, and counseling of patients. The role of a subspecialized expert cardiogenetic clinic is paramount in evaluation to navigate this complexity. Amid these intricate aspects, this review outlines potential causes of gene-elusive LQTS. It also provides an outline for the evaluation of patients with negative and inconclusive genetic test results and underscores the need for ongoing adaptation and reassessment in our understanding of LQTS, as the complexities of gene-elusive LQTS are increasingly deciphered.

Single Construct Suppression and Replacement Gene Therapy for the Treatment of All CALM1-, CALM2-, and CALM3-Mediated Arrhythmia Disorders.

BACKGROUND: CaM (calmodulin)-mediated long-QT syndrome is a genetic arrhythmia disorder (calmodulinopathies) characterized by a high prevalence of life-threatening ventricular arrhythmias occurring early in life. Three distinct genes (CALM1, CALM2, and CALM3) encode for the identical CaM protein. Conventional pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with calmodulinopathy. METHODS: Five custom-designed CALM1-, CALM2-, and CALM3-targeting short hairpin RNAs (shRNAs) were tested for knockdown (KD) efficiency using TSA201 cells and reverse transcription-quantitative polymerase chain reaction. A dual-component suppression and replacement (SupRep) CALM gene therapy (CALM-SupRep) was created by cloning into a single construct CALM1-, CALM2-, and CALM3-specific shRNAs that produce KD (suppression) of each respective gene and a shRNA-immune CALM1 cDNA (replacement). CALM1-F142L, CALM2-D130G, and CALM3-D130G induced pluripotent stem cell-derived CMs were generated from patients with CaM-mediated long-QT syndrome. A voltage-sensing dye was used to measure action potential duration at 90% repolarization (APD90). RESULTS: Following shRNA KD efficiency testing, a candidate shRNA was identified for CALM1 (86% KD), CALM2 (71% KD), and CALM3 (94% KD). The APD90 was significantly prolonged in CALM2-D130G (647±9 ms) compared with CALM2-WT (359±12 ms; P<0.0001). Transfection with CALM-SupRep shortened the average APD90 of CALM2-D130G to 457±19 ms (66% attenuation; P<0.0001). Additionally, transfection with CALM-SupRep shortened the APD90 of CALM1-F142L (665±9 to 410±15 ms; P<0.0001) and CALM3-D130G (978±81 to 446±6 ms; P<0.001). CONCLUSIONS: We provide the first proof-of-principle suppression-replacement gene therapy for CaM-mediated long-QT syndrome. The CALM-SupRep gene therapy shortened the pathologically prolonged APD90 in CALM1-, CALM2-, and CALM3-variant CaM-mediated long-QT syndrome induced pluripotent stem cell-derived CM lines. The single CALM-SupRep construct may be able to treat all calmodulinopathies, regardless of which of the 3 CaM-encoding genes are affected.

International Cohort of Neonatal Timothy Syndrome.

INTRODUCTION: Timothy syndrome (TS) is an extremely rare, multisystem disorder classically associated with long QT, syndactyly, ventricular arrhythmias, and hypoglycaemia. A neonatal diagnosis allows maximal medical and device therapy to be implemented to avoid malignant arrhythmias and sudden cardiac death. METHODS: This was a retrospective case series study of type I TS (TS1) patients using data from the Timothy Syndrome Foundation's international registry, encompassing patients with a genetic diagnosis (CACNA1C variant G406R in exon 8A) recruited over a 28-year period. RESULTS: Forty-four cases of TS1 were included (26 male; 60%). Mean gestational age (GA) was 35.6 weeks (range 28 weeks - term), with 43% of patients born less than 37 weeks GA. In TS1 patients presenting with foetal bradycardia, mean GA was significantly lower (34.2 weeks, p < 0.05). Foetal bradycardia secondary to atrioventricular block was present in 20 patients (45%), resulting in premature delivery in 14 patients (32%). Fifteen patients (34%) were diagnosed with TS1 as neonates. Long QT at birth helped secure a diagnosis in 25 patients (57%). Syndactyly was seen in most patients (n = 40, 91%). Twenty patients died, with an average age of death of 2.3 years (range 1 month-6 years). Of the 7 patients who died before the first year of life (16%), the average age of death was 2.5 months. CONCLUSION: TS is associated with high early mortality. TS should be considered in paediatric patients presenting with long QT and syndactyly. Recognition of TS in the neonatal period allows for early intervention to prevent life-threatening arrhythmias.

[Cardiac channelopathies in the context of hereditary arrhythmia syndromes]. / Kardiale Kanalopathien im Kontext hereditärer Arrhythmiesyndrome.

Genetic arrhythmia disorders are rare diseases; however, they are a common cause of sudden cardiac death in children, adolescents, and young adults. In principle, a distinction can be made between channelopathies and cardiomyopathies in the context of genetic diseases. This paper focuses on the channelopathies long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Early diagnosis of these diseases is essential, as drug therapy, behavioral measures, and if necessary, implantation of a cardioverter defibrillator can significantly improve the prognosis and quality of life of patients. This paper highlights the pathophysiological and genetic basis of these channelopathies, describes their clinical manifestations, and comments on the principles of diagnosis, risk stratification and therapy.

Torsade de pointes secondary to long QT syndrome after intragastric balloon placement. A rare but severe complication

The obesity pandemic is becoming one of the most prevalent diseases nowadays. There is a wide spectrum of treatment, ranging from hygienic-dietary measures to bariatric surgery. Endoscopic intragastric balloon placement is becoming increasingly more frequent, due to its technical simplicity, safety and short-term success(1). Although complications are rare some can be severe, so pre-endoscopic evaluation must be carried out carefully. A 43-year-old woman with a history of grade I obesity (BMI 32.7) had an Orbera® intragastric balloon implanted successfully. After the procedure she presented frequent nausea and vomiting, partially controlled with antiemetics. She attended the Emergency Department(ED) with a persistent emetic syndrome - oral intolerance and short-term loss of consciousness(syncope), for which she was admitted. Lab tests showed metabolic alkalosis with severe hypokalemia(K+ 1.8mmol/L), so fluid therapy was initiated for hydroelectrolytic replacement. During the patient’s stay in the ED, two episodes of polymorphic ventricular tachychardia “Torsades de Pointes” (PVT-TDP) occurred, leading to cardiac arrest and requiring electrical cardioversion to restore sinus rhythm, in addition to a temporary pacemaker placement. Telemetry showed a corrected QT interval of >500ms, compatible with Long QT Syndrome(LQTS). Once the patient was hemodynamically stabilized a gastroscopy was performed. The intragastric balloon located in the fundus was removed using an extraction kit, puncturing and aspirating 500ml of saline solution, and extracting the collapsed balloon without any complications. The patient achieved an adequate oral intake afterwards, and no recurrence of emetic episodes were noticed. Previous ECGs revealed a prolonged QT interval and a genetic study confirmed a congenital type 1 LQTS. Treatment was initiated with beta-blockers and a bicameral automatic defibrillator was implanted in order to prevent recurrences. ... (AU)

Implante coclear en paciente con síndrome de Q-T prolongado / Cochlear implantation in a patient with elongated Q-T syndrome / Implante coclear em paciente com síndrome de Q-T alongado

El síndrome de Q-T prolongado es una afección que se caracteriza por interrupción del ritmo cardíaco normal. Esta enfermedad es causada por mutación en genes que codifican los canales de voltaje de potasio o sodio, interrumpiendo de esta forma el flujo de dichos iones en el músculo cardíaco. En algunos casos este flujo iónico también se encuentra alterado a nivel del oído interno, por lo cual puede encontrarse asociado a hipoacusia neurosensorial profunda. El diagnóstico se basa en la electrocardiografía y el cuadro clínico, caracterizado por ataques sincopales recurrentes, crisis convulsivas o muerte súbita como primera manifestación. En los casos asociados a hipoacusia neurosensorial profunda, el implante coclear como tratamiento de la sordera presenta riesgos adicionales debido a la posibilidad de arritmias cardíacas y muerte súbita; por lo cual existen consideraciones perioperatorias especiales.

Prolonged Q-T syndrome is a condition characterized by disruption of normal heart rhythm, presented as a prolonged QT interval. This disease is caused by mutation in genes encoding the potassium or sodium voltage channels, thus disrupting the flow of such ions into the cardiac muscle. In some cases this inonic flow is also altered at the level of the inner ear, which may be associated with deep neurosensorial hearing loss. The diagnosis is based on electrocardiography and the clinical picture, characterized by recurrent syncopal attacks, seizures or sudden death as the first manifestation. In cases associated with deep neurosensory hearing loss, the cochlear implant as a treatment for deafness presents additional risks due to the possibility of cardiac arrhythmias and sudden death; for which there are special peri-operative considerations.

Síndrome Q-T prolongada é uma condição caracterizada por uma ruptura do ritmo cardíaco normal, apresentado como um intervalo prolongado de QT. Esta doença é causada por mutação em genes que codificam os canais de tensão de potássio ou de sódio, interrompendo assim o fluxo de tais íons para o músculo cardíaco. Em alguns casos, este fluxo inônico também é alterado no nível da orelha interna, o que pode estar associado à perda auditiva neurosensorial profunda. O diagnóstico é baseado em eletrocardiografia e no quadro clínico, caracterizado por ataques de síncopes recorrentes, convulsões ou morte súbita como a primeira manifestação. Nos casos associados à perda auditiva neurosensorial profunda, o implante coclear como tratamento para surdez apresenta riscos adicionais devido à possibilidade de arritmias cardíacas e morte súbita; para o qual há considerações perioperatórias especiais

Diagnóstico del síndrome de QT largo: valor del ortostatismo / Diagnosis of long QT syndrome: time to stand up

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Soporte con oxigenación de membrana extracorpórea en un síndrome de Takotsubo y QT largo tras cirugía cardiaca / Extracorporeal membrane oxygenation support for Takotsubo syndrome and long QT after cardiac surgery

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Parada cardiorrespiratoria en un paciente con SAHS / No disponible

El Síndrome de apnea hipopnea del sueño (SAHS) se contempla como una enfermedad crónica. Sin embargo, algunos pacientes con SAHS pueden presentar episodios agudos, en relación con alteraciones en la repolarización ventricular, como arritmias potencialmente mortales, parada cardiorrespiratoria e incluso muerte súbita. La repolarización ventricular se ha evaluado mediante mediciones de la onda T y el intervalo QT. El incremento de mortalidad en pacientes con SAHS, especialmente durante la noche, obliga a identificar parámetros predictores de trastornos de la repolarización miocárdica, así como evaluar un tratamiento eficaz en este tipo de pacientes donde la parada cardiorrespiratoria, puede ser el primer síntoma de esta enfermedad (AU)

Obstructive sleep apnea syndrome (OSAS) is a common chronic respiratory sleep disorder; however, patients with OSAS may occasionally present with severe cardiac arrhythmias and sudden cardiac death caused by electrical disturbances during ventricular repolarization. The assessment of ventricular repolarization has been evaluated by using T wave and QT interval measurements. Increased mortality in patients with OSAS, particularly at night, emphasizes the importance of identifying possible parameters by which OSAS could affect myocardial electrical stability and requires the study of an effective treatment in this kind of patients where the cardiac arrest, could be the first symptom of this disease (AU)

Aparente amenaza para la vida por el síndrome de QT prolongado / An apparent life threatening secondary to long Qt syndrome

Se presenta el caso de un lactante con un episodio de pérdida de conocimiento, en quien se diagnosticó fibrilación ventricular. Se realizó desfibrilación externa con éxito, permitiendo luego arribar al diagnóstico etiológico de síndrome de QT prolongado, constituyendo un ejemplo documentado de esta entidad como causa del síndrome de muerte súbita del lactante.

We report the case of an infant with an episode of loss of consciousness, in whom ventricular fibrillation was diagnosed. He was successfully defibrillated and long QT syndrome was diagnosed as his baseline disease. This case constitutes a documented example of this entity as a cause of the sudden infant death syndrome.

Aparente amenaza para la vida por el síndrome de QT prolongado / An apparent life threatening secondary to long Qt syndrome

Se presenta el caso de un lactante con un episodio de pérdida de conocimiento, en quien se diagnosticó fibrilación ventricular. Se realizó desfibrilación externa con éxito, permitiendo luego arribar al diagnóstico etiológico de síndrome de QT prolongado, constituyendo un ejemplo documentado de esta entidad como causa del síndrome de muerte súbita del lactante.(AU)

We report the case of an infant with an episode of loss of consciousness, in whom ventricular fibrillation was diagnosed. He was successfully defibrillated and long QT syndrome was diagnosed as his baseline disease. This case constitutes a documented example of this entity as a cause of the sudden infant death syndrome.(AU)

Síndrome do QT longo e torsades de pointes pós-parto / Postpartum torsades de pointes and long QT syndrome

Relatamos o caso de uma paciente puérpera, internada com diagnósticos de infecção do trato urinário e insuficiência cardíaca que evoluiu com arritmias ventriculares do tipo torsades de pointes, após hipopotassemia e uso de Ciprofloxacin. Não apresentou supressão das arritmias ventriculares após reposição de potássio e magnésio, mas após implante de marca-passo provisório. Recebeu alta hospitalar com QTc de 490 ms, em uso de Propranolol.

This article reports the case of a puerperal patient admitted with diagnosis of urinary tract infection and heart failure. This condition evolved with torsades de pointes ventricular arrhythmias, then, hypokalemia, and use of Ciprofloxacin. Ventricular arrhythmias did not present any improvement after potassium and magnesium replacement, but after implantation of temporary pacemaker, this condition showed signs of improvement. The patient was discharged with QTc at 490 ms, taking Propranolol.